Association between physical activity and mortality among breast cancer and colorectal cancer survivors: a systematic review and meta-analysis

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46. Miller VA, O’Connor P, Soh C et al. A randomized, double-blind, placebocontrolled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2009; 27(Suppl): LBA8002. 47. Kabbinavar FF, Miller VA, Johnson BE et al. Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28(Suppl): 7526. 48. Takeda K, Hida T, Sato T et al. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group Trial (WJTOG0203). J Clin Oncol 2010; 28: 753–760. 49. Gaafar RM, Surmont VF, Scagliotti GV et al. A double-blind, randomised, placebocontrolled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer 2011; 47: 2331–2340. 50. Zhang L, Ma S, Song X et al. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol 2012; 13: 466–475. 51. Garassino M, Rulli E, Marabese M et al. Prognostic and predictive role of KRAS mutations in patients with advanced non-small cell lung cancer treated with docetaxel or erlotinib as second line treatment in the TAILOR trial. Presented at the European Cancer Congress 2013, Amsterdam, Netherlands, 27 September–1 October 2013 (Abstr 32).

Annals of Oncology 25: 1293–1311, 2014 doi:10.1093/annonc/mdu012 Published online 18 March 2014

Association between physical activity and mortality among breast cancer and colorectal cancer survivors: a systematic review and meta-analysis D. Schmid* & M. F. Leitzmann Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany

Received 16 September 2013; revised 13 November 2013; accepted 3 December 2013

Background: Physical activity improves physical function during and after cancer treatment, but whether physical activity imparts survival benefit remains uncertain. Design: Using prospective studies published through June 2013, we conducted a systematic review and randomeffects meta-analysis of pre- and post-diagnosis physical activity in relation to total and cancer mortality among breast or colorectal cancer survivors. Results: Sixteen studies of breast cancer survivors and seven studies of colorectal cancer survivors yielded 49095 total cancer survivors, including 8129 total mortality cases and 4826 cancer mortality cases. Comparing the highest versus lowest levels of pre-diagnosis physical activity among breast cancer survivors, the summary relative risks (RRs) of total and breast cancer mortality were 0.77 [95% confidence interval (CI) = 0.69–0.88] and 0.77 (95% CI = 0.66–0.90, respectively. For post-diagnosis physical activity, the summary RRs of total and breast cancer mortality were 0.52 (95% *Correspondence to: Dr Daniela Schmid, Department of Epidemiology and Preventive Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Tel: +49-941-944-5245; Fax: +49-941-944-5202; E-mail: daniela.schmid@ klinik.uni-regensburg.de

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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37. Peters S, Adjei AA, Gridelli C et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23(Suppl 7): vii56–vii64. 38. Azzoli CG, Baker S, Jr, Temin S et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009; 27: 6251–6266. 39. Smith IE, O’Brien MER, Talbot DC et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001; 19: 1336–1343. 40. von Plessen C, Bergman B, Andresen O et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. Br J Cancer 2006; 95: 966–973. 41. Park JO, Kim SW, Ahn JS et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non-small-cell lung cancer. J Clin Oncol 2007; 25: 5233–5239. 42. Westeel V, Quoix E, Moro-Sibilot D et al.; French Thoracic Oncology Collaborative Group (GCOT). Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer. J Natl Cancer Inst 2005; 97: 499–506. 43. Fidias PM, Dakhil SR, Lyss AP et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009; 27: 591–598. 44. Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–1440. 45. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 2010; 11: 521–529.

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introduction Breast cancer represents the number one cause of cancer incidence and mortality in women, with 1.38 million new breast cancer cases and 458 400 breast cancer deaths estimated to have occurred in 2008 [1]. Colorectal cancer is the second most frequently diagnosed cancer in women and the third most frequently diagnosed cancer in men, accounting for 1.23 million new colorectal cancer cases and 608 700 colorectal cancer deaths in 2008. The number of cancer survivors continues to increase due to population aging, earlier diagnosis through improved screening, and advances in modern cancer treatment [2]. The estimated number of individuals with a history of cancer living in the USA was 13.7 million in 2012 and is expected to increase to nearly 18 million by 2022. The 5-year survival rate for breast cancer patients among females improved from 75.1% between 1975 and 1977 to 90% between 2001 and 2007 [2]. Likewise, the 5-year colon cancer survival rate for men increased from 48.9% between 1975 and 1977 to 66.1% between 2003 and 2009 [3]. For women, colon cancer survival increased from 50.6 to 65.7% during that time. Physical activity is an important determinant of beneficial health conditions among cancer survivors [4], but whether physical activity improves cancer survival remains inadequately understood. Of cancer sites investigated thus far, breast cancer and colorectal cancer have been the most extensively studied. Specifically, 16 prospective studies examined physical activity in relation to survival among individuals with a history of breast cancer [5–20] and seven prospective studies investigated the association between physical activity and survival among individuals with colorectal cancer [21–27]. Most of those investigations reported an inverse association between physical activity and total or cancer mortality [5, 9–14, 16–23, 25–27], although two studies reported a null relation [6, 15] and one study found a positive association [8]. The aim of the current systematic review and meta-analysis was to quantify the evidence from prospective studies of physical activity in relation to total mortality and cancer mortality among survivors of breast cancer or colorectal cancer. Our study differs from two previous meta-analyses on this topic [28, 29] in quantifying the effect size per increment of physical activity, examining change in physical activity from pre- to post-diagnosis in relation to mortality among cancer survivors, and

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performing meta-regression analyses to evaluate potential sources of heterogeneity between studies.

materials and methods literature search and inclusion criteria Our meta-analysis was conducted according to the Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) guidelines [30]. A comprehensive literature search was carried out in PubMed from the earliest possible year to June 2013 using the following search terms: ((((( physical activity) OR motor activity) OR exercise)) AND ((((breast cancer) OR colorectal cancer) OR colon cancer) OR rectal cancer)) AND ((((survival) OR survivor) OR mortality) OR recurrence). In addition, we reviewed the bibliographic lists of retrieved articles for relevant studies. Studies were included if they met the following criteria: they (1) were original human studies published in English; (2) investigated the association between physical activity and risk of total mortality or cancer mortality among breast cancer or colorectal cancer survivors; (3) provided relative risk (RR) estimates and 95% confidence intervals (CIs) or data to calculate them; (4) were at least matched or adjusted for age. If datasets were found to overlap among publications, we included the article with the largest sample size. Studies were excluded if the exposure was physical activity combined with another exposure. We also excluded studies that examined the combination of cancer recurrence and cancer mortality.

data extraction Both authors independently assessed the eligibility of studies and any discrepancies were resolved by consensus. From each article, the following information was extracted: first author’s name, publication year, study geographic location, number of study participants and cases, specific outcomes, measures of exposure, adjustment factors, and RRs with corresponding 95% CIs. If more than one risk estimate was reported in the same article, we chose the most fully adjusted estimate. The effect size and 95% CI were inverted when the most active group was used as the reference group.

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CI = 0.42–0.64) and 0.72 (95% CI = 0.60–0.85), respectively. For pre-diagnosis physical activity among colorectal cancer survivors, the summary RRs of total and colorectal cancer mortality were 0.74 (95% CI = 0.63–0.86) and 0.75 (95% CI = 0.62–0.91), respectively. For post-diagnosis physical activity, the summary RRs of total and colorectal cancer mortality were 0.58 (95% CI = 0.48–0.70) and 0.61 (95% CI = 0.40–0.92), respectively. Each 10 metabolic equivalent task-hour/ week increase in post-diagnosis physical activity (equivalent to current recommendations of 150 min/week of at least moderate intensity activity) was associated with 24% (95% CI = 11–36%) decreased total mortality risk among breast cancer survivors and 28% (95% CI = 20–35%) decreased total mortality risk among colorectal cancer survivors. Breast or colorectal cancer survivors who increased their physical activity by any level from pre- to post-diagnosis showed decreased total mortality risk (RR = 0.61; 95% CI = 0.46–0.80) compared with those who did not change their physical activity level or were inactive/insufficiently active before diagnosis. Conclusion: Physical activity performed before or after cancer diagnosis is related to reduced mortality risk among breast and colorectal cancer survivors. Key words: cancer, meta-analysis, physical activity, survival

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statistical analysis

results literature search and description of the studies Our literature search yielded 1297 publications in PubMed and 1 article identified by manual search (Figure 1). Based on the screening of titles and abstracts, 32 articles remained for full review. Of these, we excluded nine studies because they provided information from overlapping studies or combined physical activity with other exposures. A total of 16 studies on breast cancer survival [5–20] and 7 studies on colorectal cancer survivors [21–27] remained and were included in our meta-analysis. The total number of individuals in the studies was 49095, including 8129 cases of total mortality and 4826 cases of cancer mortality. Most investigations focused on recreational physical activity with the exception of 1 study that explored total physical activity [25]. Physical activity was expressed as times per week, hours per week, MET-hours per week, or energy expenditure in calories per week. The number of adjustment factors ranged from 2 to 16 (Table 1).

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1297 articles identified in PubMed

1 article identified from reference lists

1298 articles identified 1266 articles excluded that were not related to physical activity or total or recurrence among cancer survivors

32 articles identified for full review 6 duplicate studies 3 combined exposures

23 articles included in the meta-analysis Figure 1. Flow diagram of the literature search strategy and study selection for the meta-analysis.

breast cancer survivors pre- and post-diagnosis physical activity. Among breast cancer survivors, high versus low pre-diagnosis physical activity was associated with decreased risks of total mortality (RR = 0.77; 95% CI = 0.69–0.88) and breast cancer mortality (RR = 0.77; 95% CI = 0.66–0.90) (Figures 2 and 3). There was no statistically significant heterogeneity among studies (total mortality: I 2 = 41%; Pheterogeneity = 0.08; breast cancer mortality: I 2 = 30%; Pheterogeneity = 0.16). High versus low post-diagnosis physical activity was also related to decreased risk of total mortality (RR = 0.52; 95% CI = 0.42–0.64) and breast cancer mortality (RR = 0.72; 95% CI = 0.60–0.85). No heterogeneity among studies was observed (total mortality: I 2 = 34%; Pheterogeneity = 0.22; breast cancer mortality: I 2 = 0%; Pheterogeneity = 0.43). We found no evidence of publication bias by visual inspection of the funnel plot, Begg’s test (P = 0.33), and Egger’s test (P = 0.20). Removal of one study at a time did not substantially alter the results (supplementary Table S1, available at Annals of Oncology online, for total mortality, supplementary Table S2, available at Annals of Oncology online, for cancer mortality). A sensitivity analysis investigating post-diagnosis physical activity measured within 1–2 years of breast cancer diagnosis did not materially change the findings (total mortality: RR = 0.57; 95% CI = 0.49– 0.67; breast cancer mortality: RR = 0.71; 95% CI = 0.58–0.86). stratification by BMI, menopausal status, and tumor ER status. The association between pre- or post-diagnosis physical activity and total mortality among breast cancer survivors did not differ according to BMI, menopausal status, or tumor ER status (all Pheterogeneity > 0.05; Table 2). We noted a more pronounced inverse association between the combination of pre- and post-

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We estimated pooled RRs comparing the highest versus lowest categories of physical activity before and after diagnosis and change in physical activity from pre- to post-diagnosis in relation to total or cancer mortality among breast and colorectal cancer survivors using random-effects models [31]. We prioritized risk estimates of lifetime or long-term physical activity measures over recent physical activity measures. We focused on recreational physical activity because it represents the main modifiable aspect of energy expenditure. We calculated the Q-statistic to test for between-study heterogeneity and we used the I²-statistic to quantify the proportion of the total variation due to heterogeneity [31]. Potential publication bias was assessed by visual inspection of funnel plots and by using Egger’s regression test [32] and Begg’s rank correlation test [33]. Sources of potential heterogeneity among studies were explored using random-effects meta-regression. We performed sensitivity analyses omitting one study at a time from the initial meta-analysis. We addressed the potential for reverse causation to the extent possible by conducting subanalyses including only studies where post-diagnosis physical activity was measured within 1–2 years of breast or colorectal cancer diagnosis. In an additional analysis, we investigated the association between physical activity and total and cancer mortality among subgroups of breast cancer survivors defined by levels of body mass index (BMI), menopausal status, and estrogen receptor (ER) status. We lacked corresponding data for colorectal cancer survivors. We also examined the relation of physical activity to total mortality among breast and colorectal cancer survivors using physical activity as a continuous variable. We pooled risk estimates of physical activity in increments of 5, 10, or 15 metabolic equivalent task (MET)-h/week using generalized least-squares trend estimation as described by Orsini et al. [34]. All statistical analyses were performed using the R-package ‘metafor’ [35] and SAS version 9.2. P-values were two-sided and were considered significant at α = 0.05.

Author, year, (country)

Cancer type, stage

Rohan et al. [5], Breast cancer 1995 (Australia)

Outcome

Study design, subjects/ Follow-up cases, sex duration

PA before/ Category and timing of PA measurement after diagnosis

Main result: RR (95% CI)

Cancer mortality

Follow-up of a population-based case–control study, 411/112 women

2010 days

Before

0 >0 and ≤2000 >2000 ≤4000 >4000

Prospective cohort study, 602/112 women

Approx. 10 After years

>1 versus 0/week of selfreported recreational PA at baseline

>4000 versus 0 kcal/week of interview-assessed recreational PA during the summer and winter seasons 1 year before diagnosis

Breast cancer Cancer mortality stage: ductal carcinoma in situ, I, II, II

Enger et al. [7], 2004 (USA)

Breast cancer stage: in situ, localized, regional, distant Breast cancer stage: local, distant, regional

Cancer mortality

Follow-up of a population-based case–control study, 717/251 women

10.4 years

Before

3.8+ versus 0 h/week of interview-assessed recreational PA from first menses to reference date

Total mortality

Prospective cohort study, 1230/285 women

8.5 years

Before

Colorectal cancer, stage: I–IV

Total Prospective cohort mortality, study, total cancer mortality: 526/208 mortality men and women cancer mortality: 526/181 men and women Total Prospective cohort mortality study, 832/84 men and women

5.5 years

Before

Quartiles (Q) 4 (43.1–98.0) versus Q1 (1.6–16.6) of relative units/week of interview-assessed recreational PA during the three periods before diagnosis For BMI stratification: high versus low recent PA (median as the cut-point) >1 versus 0 times/week of interview-assessed nonoccupational PA 6 months before baseline

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Haydon et al. [21], 2006 (USA)

Meyerhardt et al. [22], 2006,

Colon cancer, stage: III

After

≥27 versus <3 MET-h/week of self-reported recreational PA ∼6

Q1 (1.6–16.6) Q2 (16.7–29.4) Q3 (29.5–43.0) Q4 (43.1–98.0)

Total mortality: 0 times/week >1 times/week Cancer mortality: 0 times/week >1 times/week <3 3–8.9 9–17.9

1.0 Income, cancer stage (age was not 0.84 (0.60–1.18) included in the final model as it 0.97 (0.70–1.35) was found not be a confounder) 1.16 (0.84–1.60)

Sex, age, cancer stage 1.00 0.77 (0.58–1.03) 1.00 0.73 (0.54–1.00) 1.00 Sex, age, depth of invasion 0.85 (0.49–1.49) through bowel wall, number of 0.71 (0.36–1.41) positive lymph nodes, presence

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Abrahamson et al. [8], 2006 (USA)

1.0 Age, ER, and PR status, tumor 1.42 (0.78–2.60) diameter, years of education, 0.73 (0.37–1.42) history of benign breast disease, 0.98 (0.50–1.94) age at menarche, age at first live birth, height, Quetelet’s index, energy intake, menopausal status Total energy intake, age, stage at 1.0 None diagnosis A few times/year 1.4 (0.7–2.6) 2.2 (1.2–4.0) A few times/ month About once/week 1.3 (0.7–2.3) More than once/ 1.0 (0.6–1.6) week Age, cancer stage, BMI 1.00 0 0.86 (0.56–1.32) 0.1-0.70 0.59 (0.35–1.01) 0.8-1.6 0.87 (0.57–1.33) 1.7-3.7 1.30 (0.81–2.09) 3.8+

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Borugian et al. [6], 2004 (Canada)

Adjustment factors

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Table 1. Characteristics of the 23 studies included in the meta-analysis

Breast cancer, stage: I–IV

Total mortality, cancer mortality

Prospective cohort study, total mortality: 573/ 132 women cancer mortality: 573/ 80 women

9.6 years

12.6 years Total Follow-up of a mortality, multicenter cancer hospital-based case– mortality control study, total mortality: 1380/478 men and women cancer mortality: 1380/376

Before, after

Before

≥18 versus <3 MET-h/week of self-reported recreational PA 6 months before diagnosis and 1–4 years after diagnosis

Total mortality: pre-diagnosis: <3 3–8.9 9.0–17.9 ≥18 post-diagnosis: <3 3–8.9 9.0–17.9 ≥18 Cancer mortality: pre-diagnosis: <3 3–8.9 9.0–17.9 ≥18 post-diagnosis: <3 3–8.9 9.0–17.9 ≥18 ≥2 versus <2 h/week of Total mortality: recent self-reported <2 recreational PA at baseline ≥2 Cancer mortality: <2 ≥2

0.71 (0.32–1.59) 0.37 (0.16–0.82)

of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline CEA, tumor grade, baseline performance status, treatment arm, weight change between first and second questionnaire, BMI at time of second questionnaire, time between study entry and completion of second questionnaire Age at diagnosis, BMI, change in BMI before and after diagnosis, 1.0 cancer stage, cancer grade, 0.85 (0.52–1.37) colon or rectal primary, year of 1.14 (0.69–1.87) diagnosis, receipt of 0.95 (0.57–1.59) chemotherapy, time from diagnosis to PA measurement, 1.0 smoking status 0.77 (0.48–1.23) 0.50 (0.28–0.90) 0.43 (0.25–0.74)

1.0 0.83 (0.45–1.53) 1.05 (0.56–1.99) 0.86 (0.44–1.67) 1.0 0.92 (0.50–1.69) 0.57 (0.56–1.20) 0.39 (0.18–0.82) 1.0 0.82 (0.67–1.01)

Region of residence, age at diagnosis, year at diagnosis, TNM stage, ER/PR status

1.0 0.85 (0.68–1.07)

Continued

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Dal Maso et al. [9], 2008 (Italy)

Colorectal cancer, stage: I–III

18–26.9 ≥27

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Meyerhardt et al. [23], 2006, NHS (USA)

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CALGB (USA)

Author, year, (country)

Cancer type, stage

Outcome

Holick et al. [10], 2008 (USA)

Breast cancer, stage: local, regional

6 years Total Follow-up of three mortality, population-based cancer case–control studies, mortality total mortality: 4482/412 men and women cancer mortality: 4482/109 men and women

After

6 years Total Prospective cohort mortality, study, cancer total mortality: 933/ mortality 164 women cancer mortality: 933/115 women

Before, after

Breast cancer, stage: 0–III

Total Prospective cohort mortality, study, cancer total mortality: mortality 1225/341 women cancer mortality: 1225/225 women

8.3 years

Before

≥21.0 versus <2.8 MET-h/ week of self-reported recent recreational PA after diagnosis For BMI stratification: ≥8.0 versus <8.0 MET-h/ week

≥9 versus 0 MET-h/week of interview-assessed recreational PA 1 year before diagnosis and 3 years after diagnosis

Main result: RR (95% CI)

Adjustment factors

Total mortality: <2.8 2.8- 7.9 8.0-20.9 ≥21.0 Cancer mortality: <2.8 2.8-7.9 8.0- 20.9 ≥21.0

Age at diagnosis, cancer stage at diagnosis, state of residence at diagnosis, interval between diagnosis and PA assessment, post-diagnosis BMI, postdiagnosis menopausal status, post-diagnosis HRT, total energy intake in the year before enrollment in the study, education level at diagnosis, family history of breast cancer at diagnosis, initial treatment modality Age, race, cancer stage, initial treatment, tamoxifen use (postdiagnosis: additionally adjusted for BMI, fruit/vegetable servings per day)

Total mortality: pre-diagnosis: 0 0–8.9 ≥9 post-diagnosis: 0 0–8.9 ≥9 Cancer mortality: pre-diagnosis: 0 0–8.9 ≥9 post-diagnosis: 0 0–8.9 ≥9 >19 versus ≤5 MET-h/week/ Total mortality: year of interview-assessed ≤5 lifetime recreational PA >5≤10 before diagnosis >10≤19 >19 Cancer mortality: ≤5 >5≤10

1.0 0.58 (0.45–0.76) 0.53 (0.40–0.69) 0.44 (0.32–0.60) 1.0 0.65 (0.39–1.08) 0.59 (0.35–1.01) 0.51 (0.29–0.89)

1.0 1.14 (0.75–1.74) 0.69 (0.45–1.06) 1.0 0.36 (0.17–0.73) 0.33 (0.15–0.73)

1.0 1.31 (0.80–1.85) 0.83 (0.49–1.38) 1.0 0.72 (0.28–1.85) 0.65 (0.23–1.87) Occupational activity, household activity, age, tumor stage, treatment, Scarff-BloomRichardson grade, (total mortality: additionally adjusted for WHR, HRT use, oral contraceptive use, weight gain 1.0 since age 20, total pack-years of 0.68 (0.47–0.98) smoking for current and former 1.0 0.66 (0.48–0.89) 0.71 (0.52–0.97) 0.73 (0.53–1.00)

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Friedenreich et al. [12], 2009 (Canada)

PA before/ Category and timing of PA after measurement diagnosis

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Irwin et al. [11], Breast cancer, 2008 (USA) stage: local, regional

Study design, subjects/ Follow-up cases, sex duration

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Table 1. Continued

Colorectal cancer, stage: I–III

8.6 years Total Prospective cohort mortality, study, cancer total mortality: 661/ mortality 258 men cancer mortality: 661/88 men

After

West-Wright et al. [13], 2009 (USA)

Breast cancer, stage: localized, nonlocalized

Total Prospective cohort mortality, study, cancer total mortality: mortality 3539/460 women cancer mortality: 3539/221 women

38.5 months

Before

Emaus et al. [14], 2010 (Denmark)

Breast cancer, stage: I–IV

Total Prospective cohort mortality, study, cancer total mortality: mortality 1364/429 women cancer mortality: 1364/355 women

8.2 years

Before

7.8 years Total Prospective cohort mortality, study, cancer total mortality: 528/ mortality 323 women cancer mortality: 420/178 women

Before

Total mortality

Before

Keegan et al. [16], 2010 (USA )

Breast cancer

Prospective cohort study, 3833/605 women

7.8 years

>4 versus 0 h/week selfreported recreational PA before diagnosis

Total mortality: Inactive 2–4 h/week >4 h/week Cancer mortality: Inactive 2–4 h/week >4 h/week >46.0 versus ≤6.7 MET-h/ Total mortality: week of self-reported Q1: ≤6.7 recreational PA three years Q2: 6.8–16.3

1.00 1.07 (0.77–1.49) 1.00 (0.69–1.45)

Alcohol intake, smoking, BMI, HRT, age, cancer stage, menopausal status, parity, education, adjuvant treatment

1.00 0.83 (0.55–1.27) 1.01 (0.62–1.63) 1.00 0.86 (0.76–1.11)

Study center, age of diagnosis, race/ethnicity, number of affected nodes, BMI, time since Continued

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Hellmann et al. Breast cancer, [15], 2010 stage: local, (Denmark) regional, metastatic

smokers; for cancer mortality: additionally for PR status, WHR, HRT use) Age at diagnosis, cancer stage, >27 versus ≤ 3 MET-h/week Total mortality: cancer grade, colon or rectal 1.0 of self-reported ≤3 primary, year of diagnosis, BMI, 1.0 (0.68–1.48) recreational PA 4 months 3.1–9 time from diagnosis to PA 1.12 (0.74–1.70) to 4 years after diagnosis 9.1–18 measurement, change in BMI 0.74 (0.46–1.20) 18.1–27 before and after diagnosis, 0.59 (0.41–0.86) >27 smoking status Cancer mortality: 1.0 ≤3 1.06 (0.55–2.08) 3.1–9 1.30 (0.65–2.59) 9.1–18 0.76 (0.33–1.77) 18.1–27 0.47 (0.24–0.92) >27 Age, race, BMI, total energy >3 h versus >0.5 h/week/y of Total mortality: intake, number of comorbid 1.0 >0.5 recent PA (combined conditions, ER status 0.83 (0.65–1.07) >0.5-≤3 moderate and strenuous 0.73 (0.55–0.96) >3 PA) 3 years before study Cancer mortality: entry 1.0 >0.5 0.65 (0.45–0.93) >0.5-≤3 0.53 (0.35–0.80) >3 Age at diagnosis, pre-diagnostic Total mortality: Hard versus sedentary selfobservation time, tumor stage, 1.0 Sedentary reported recreational PA region of residence, calendar 0.88 (0.70–1.11) Moderate in the year preceding a year before and after 1995, BMI 0.74 (0.51–1.08) Hard screening mammogram Cancer mortality: For BMI stratification: 1.0 Sedentary regular versus sedentary 0.92 (0.71–1.19) Moderate recent recreational PA 0.75 (0.49–1.15) Hard

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Meyerhardt et al. [24], 2009 (USA)

0.65 (0.45–0.94) 0.54 (0.36–0.79)

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>10≤19 >19

Baade et al. [25], 2011 (Australia)

Cancer type, stage

Colorectal cancer, stage: I–III

Irwin et al. [17], Breast cancer 2011 (USA)

Breast cancer

Study design, subjects/ Follow-up cases, sex duration

Total Prospective cohort mortality, study, cancer total mortality: mortality 1825/462 men and women cancer mortality: 1825/345

4.9 years

Total Prospective cohort mortality, study, cancer total mortality: mortality 4643/350 women cancer mortality: 4643/194 women

3.3 years

Total Prospective cohort mortality, study, cancer total mortality: mortality 1451/192 women

66.7 months

PA before/ Category and timing of PA after measurement diagnosis

After

Before, after

Before

before diagnosis for BMI stratification: 17.7 versus 0 MET-h/week Sufficiently active total PA versus sedentary 5 months after diagnosis

Main result: RR (95% CI)

Q3: 16.4–26.1 Q4: 26.2–46.0 Q5 > 46.0 Total mortality: Sedentary Insufficiently active Sufficiently active Cancer mortality: Sedentary Insufficiently active Sufficiently active 9+ versus 0 MET-h/week of Total mortality: self-reported recreational pre-diagnosis: MVPA at baseline (pre0 diagnosis PA) and 3 or 6 1–3.0 years after diagnosis 3.1–8.9 For BMI stratification: >0 9+ versus 0 MET-h/week post-diagnosis: 0 1–3.0 9+ Cancer mortality: pre-diagnosis: 0 1–3.0 3.1–8.9 9+ post-diagnosis: 0 1–3.0 3.1–8.9 9+ ≥ 9 versus 0 MET-h/week of Total mortality: interview-assessed lifetime 0 recreational PA before >0 to <9 diagnosis ≥9

Adjustment factors

0.84 (0.46–1.10) 0.88 (0.68–1.14) 0.93 (0.72–1.21)

last full pregnancy, ER status, PR status, tumor grade, tumor size, tumor type Sex, age, BMI, smoking status, marital status, education level, 1.00 private health insurance, site, 0.72 (0.57–0.91) stage of disease, treatment, 0.75 (0.60–0.94) comorbidities 1.00 0.90 (0.69–1.17) 0.88 (0.68–1.15)

1.00 0.81 (0.56–1.16) 0.67 (0.50–0.91) 0.61 (0.47–0.81) 1.00 0.72 (0.48–1.07) 0.54 (0.38–0.79)

Age, ethnicity, study arm, previous HRT, BMI, diabetes, alcohol, smoking, intakes of total energy, percent energy from fat, and servings of fruits and vegetables (post-diagnosis: additionally adjusted for stage, ER, PR, grade, HER2, time from diagnosis to PA assessment)

1.00 0.83 (0.51–1.37) 0.82 (0.55–1.22) 0.71 (0.49–1.03) 1.00 0.30 (0.09–0.99) 0.77 (0.43–1.38) 0.61 (0.35–0.99) 1.00 0.59 (0.42–0.82) 0.57 (0.39–0.83)

Age at diagnosis, BMI, menopausal status

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Cleveland et al. [18], 2012 (USA)

Outcome

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Author, year, (country)

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Table 1. Continued

Kuiper et al. [26], 2012 (USA)

Colorectal cancer, stage:

Total Multicenter mortality, prospective cancer cohort study, mortality total mortality: 1339/265 women cancer mortality: 1339/171 women

Total Prospective cohort mortality, study, total mortality:

11.9 years

6.8 years

Before, after

Before, after

≥18 versus 0 METh/week of self-reportassessed recreational PA ∼5.6 years before diagnosis and 1.5 years after diagnosis

≥8.75 versus <3.5 MET-h/week of recreational PA

Total mortality: Pre-diagnosis: 0 >0–2.9 3.0–8.9 9.0–17.9 ≥18.0 post-diagnosis: 0 >0–2.9 3.0–8.9 9.0–17.9 ≥18.0 Cancer mortality: pre-diagnosis: 0 >0–2.9 3.0–8.9 9.0–17.9 ≥18.0 post-diagnosis: 0 >0–2.9 3.0–8.9 9.0–17.9 ≥18.0 Total mortality: pre-diagnosis: <3.5

1.00 0.90 (0.77–1.04) 0.77 (0.66–0.90)

Age at diagnosis, race, menopausal status, TNM stage, hormone receptor status, treatment, postdiagnosis BMI, smoking status

0.71 (0.60–0.84) 0.60 (0.51–0.72)

1 0.93 (0.61–1.43) 1.01 (0.71–1.43) 0.77 (0.52–1.12) 0.63 (0.42–0.96)

Age at diagnosis, study arm, BMI (post-diagnosis, pre-diagnosis), tumor stage, ethnicity, education, alcohol, smoking, and HRT (post-diagnosis: additionally adjusted for time from diagnosis to measurement)

1 0.71 (0.40–1.30) 0.42 (0.23–0.77) 0.57 (0.31–1.07) 0.41 (0.21–0.81)

1.00 0.98 (0.58–1.66) 1.01 (0.65–1.57) 0.74 (0.46–1.20) 0.68 (0.41–1.13) 1.00 0.49 (0.21–1.14) 0.30 (0.12–0.73) 0.53 (0.22–1.25) 0.29 (0.11–0.77) Age at diagnosis, smoking status, BMI, red meat intake, cancer 1.00 Continued

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Campbell et al. [27], 2013 (USA)

Colorectal cancer, stage: localized, regional

Not After Total Four prospective provided mortality, cohort studies, cancer total mortality: mortality 11 315/1468 women; Cancer mortality: 11 282/971 women

0.61 (0.40–0.92) 0.66 (0.42–1.06)

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Beasley et al. Breast cancer [19], 2012 (USA, China)

Cancer mortality: 0 1.00 >0 to <9 ≥9 36.5 versus 0 MET-h/week of Total mortality: 0 MET-h/week recreational PA 18–48 3.7 MET-h/week months after diagnosis for BMI and menopausal 10.0 MET-h/ status stratification: ≥10.0 week versus<10.0 MET-h/week 18.7 MET-h/ week 36.5 MET-h/ week

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cancer mortality: 1225/120 women

Author, year, (country)

Cancer type, stage localized, regional

Schmidt et al. [20], 2013 (Germany)

Outcome

cancer mortality

Study design, subjects/ Follow-up cases, sex duration

PA before/ Category and timing of PA after measurement diagnosis assessed 7 years before diagnosis and 1.7 and 2.3 years after diagnosis

2293/846 men and women cancer mortality: 2293/379 men and women

Breast cancer, Total Prospective cohort stage: I–IIIa mortality, study, cancer total mortality: mortality 3393/367 women cancer mortality: 3393/243 women

5.6 years

Before

≥42 versus 0 METh/week of recent recreational PA assessed at ≥50 years of age until diagnosis

Main result: RR (95% CI)

3.5–8.74 ≥8.75 post-diagnosis: <3.5 3.5–8.74 ≥8.75 Cancer mortality: pre-diagnosis: <3.5 3.5–8.74 ≥8.75 post-diagnosis: <3.5 3.5–8.74 ≥8.75

Total mortality: 0 >0 to <12 12 to <24 24 to <42 ≥42

0.69 (0.55 –0.85) 0.72 (0.58 –0.89)

Adjustment factors

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 | Schmid and Leitzmann

Table 1. Continued

stage, leisure-time spent sitting, education

1.00 0.78 (0.60 –1.00) 0.58 (0.47 –0.71)

1.00 0.68 (0.49–0.95) 0.78 (0.57–1.08) 1.00 1.00 (0.64–1.56) 0.87 (0.61 –1.24)

1.00 0.67 (0.50–0.90) 0.76 (0.55–1.04) 0.77 (0.56–1.07) 0.66 (0.47–0.92)

For BMI stratification: any versus no PA

RR, relative risk; CI, confidence interval; PA, physical activity; MVPA, moderate to vigorous physical activity; MET, metabolic equivalent of task; BMI, body mass index; WHR, waist to hip ratio; HRT, hormone replacement therapy; CEA, carcinoembryonic antigen; ER, estrogen receptor; PR, progesterone receptor.

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Tumor size, nodal status, tumor grade, ER/PR status, radiotherapy, screen-detected tumor, HT use at diagnosis, age at diagnosis, BMI pre-diagnosis, smoking status and pack-years, pre-existing angina pectoris (for total mortality: additionally adjusted for pre-existing hypertension, previous stroke, and insulin therapy)

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Annals of Oncology

Authors, year (Gender)

Relative risk [95% CI]

Breast cancer (pre−diagnosis PA) 0.57 [0.39, 0.83] 0.61 [0.47, 0.81] 0.66 [0.47, 0.92] 0.69 [0.45, 1.06] 0.73 [0.53, 1.00] 0.73 [0.55, 0.96] 0.74 [0.51, 1.08] 0.82 [0.67, 1.01] 0.93 [0.72, 1.21] 1.00 [0.69, 1.45] 1.16 [0.84, 1.60]

Random effects model

0.77 [0.69, 0.88]

Breast cancer (post−diagnosis PA) Irwin et al., 2008 (women) Holick et al., 2008 (women) Irwin et al., 2011 (women) Beasley et al., 2012 (women)

0.33 [0.15, 0.73] 0.44 [0.32, 0.60] 0.54 [0.38, 0.79] 0.60 [0.51, 0.72]

Random effects model

0.52 [0.42, 0.64]

Colorectal cancer (pre−diagnosis PA) Kuiper et al., 2012 (women) Campbell et al., 2013 (women and men) Haydon et al., 2006 (men and women) Meyerhardt et al., 2006, NHS (women)

0.63 [0.42, 0.96] 0.72 [0.58, 0.89] 0.77 [0.58, 1.03] 0.95 [0.57, 1.59]

Random effects model

0.74 [0.63, 0.86]

Colorectal cancer (post−diagnosis PA) Meyerhardt et al., 2006, CALGB (men and women) Kuiper et al., 2012 (women) Meyerhardt et al., 2006, NHS (women) Campbell et al., 2013 (women and men) Meyerhardt et al., 2009 (men) Baade et al., 2011 (men and women)

0.37 [0.16, 0.82] 0.41 [0.21, 0.81] 0.43 [0.25, 0.74] 0.58 [0.47, 0.71] 0.59 [0.41, 0.86] 0.75 [0.60, 0.94]

Random effects model

0.58 [0.48, 0.70]

0.25

0.50

1.00

2.00

4.00

Relative risk (log scale) Figure 2. Forest plot of the relation between physical activity (PA) and total mortality stratified by cancer site.

diagnosis physical activity and breast cancer mortality among post-menopausal women (RR = 0.71; 95% CI = 0.62–0.82) than pre-menopausal women (RR = 0.96; 95% CI = 0.74–1.23) (Pdifference = 0.04). dose–response relation between physical activity and total mortality and cancer mortality. Each 5, 10, or 15 MET-h/week increase in pre-diagnosis physical activity was related to a 7% (95% CI = 2–12%), 13% (95% CI = 4–21%), and 19% (95% CI = 6–30%) reduction in risk of total mortality among breast

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cancer survivors, respectively (Table 3). Each 5, 10, or 15 METh/week increase in post-diagnosis physical activity was associated with a 13% (95% CI = 6–20%), 24% (95% CI = 11– 36%), and 34% (95% CI = 16–38%) decreased risk of total mortality, respectively. The risk estimates for increments of 5, 10, or 15 MET-h/week in pre-diagnosis physical activity in relation to cancer mortality among breast cancer survivors were similar to those seen for total mortality (Table 3). Each 5, 10, or 15 MET-h/week increase in post-diagnosis physical activity revealed a 6% (95% CI = 3–8%), 11% (95% CI = 6–15%), and

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Cleveland et al., 2012 (women) Irwin et al., 2011 (women) Schmidt et al., 2013 (women) Irwin et al., 2008 (women) Friedenreich et al., 2009 (women) West−Wright et al., 2009 (women) Emaus et al., 2010 (women) Dal Maso et al., 2008 (women) Keegan et al., 2010 (women) Hellmann et al., 2010 (women) Abrahamson et al., 2006 (women)

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Annals of Oncology

Authors, year (Gender)

Relative risk [95% CI]

Breast cancer (pre−diagnosis PA) 0.53 [0.35, 0.80] 0.54 [0.36, 0.79] 0.66 [0.42, 1.06] 0.71 [0.49, 1.03] 0.75 [0.49, 1.15] 0.78 [0.45, 1.34] 0.80 [0.53, 1.21] 0.83 [0.49, 1.38] 0.85 [0.68, 1.07] 0.98 [0.50, 1.94] 1.01 [0.62, 1.63]

Random effects model

0.77 [0.66, 0.90]

Breast cancer (post−diagnosis PA) Holick et al., 2008 (women) Irwin et al., 2011 (women) Irwin et al., 2008 (women) Beasley et al., 2012 (women) Borugian et al., 2004 (women)

0.51 [0.29, 0.89] 0.61 [0.35, 0.99] 0.65 [0.23, 1.87] 0.73 [0.59, 0.91] 1.00 [0.60, 1.60]

Random effects model

0.72 [0.60, 0.85]

Colorectal cancer (pre−diagnosis PA) Kuiper et al., 2012 (women) Haydon et al., 2006 (men and women) Campbell et al., 2013 (women and men) Meyerhardt et al., 2006 (women)

0.68 [0.41, 1.13] 0.73 [0.54, 1.00] 0.78 [0.57, 1.08] 0.86 [0.44, 1.67]

Random effects model

0.75 [0.62, 0.91]

Colorectal cancer (post−diagnosis PA) Kuiper et al., 2012 (women) Meyerhardt et al., 2006 (women) Meyerhardt et al., 2009 (men) Campbell et al., 2013 (women and men) Baade et al., 2011 (men and women)

0.29 [0.11, 0.77] 0.39 [0.18, 0.82] 0.47 [0.24, 0.92] 0.87 [0.61, 1.24] 0.88 [0.68, 1.15]

Random effects model

0.61 [0.40, 0.92]

0.25

0.50

1.00

2.00

4.00

Relative risk (log scale) Figure 3. Forest plot of the relation between physical activity (PA) and cancer mortality stratified by cancer site.

16% (95% CI = 9–22%) reduction in risk of cancer mortality among breast cancer survivors, respectively.

colorectal cancer survivors pre- and post-diagnosis physical activity. Colorectal cancer survivors with high versus low levels of pre-diagnosis physical activity showed decreased risks of total mortality (RR = 0.74; 95% CI = 0.63–0.86) and colorectal cancer mortality (RR = 0.75; 95%, CI = 0.62–0.91; Figures 2 and 3). No heterogeneity among studies

 | Schmid and Leitzmann

was observed (total mortality: I² = 0%; Pheterogeneity = 0.66; cancer mortality: I 2 = 0%; Pheterogeneity = 0.94). High versus low postdiagnosis physical activity showed strong risk reductions for both total mortality (RR = 0.58; 95% CI = 0.48–0.70) and colorectal cancer mortality (RR = 0.61; 95% CI = 0.40–0.92). For total mortality, no significant heterogeneity among studies was observed (I 2 = 40%; Pheterogeneity = 0.16), whereas there was some evidence of heterogeneity among studies for colorectal cancer mortality (I 2 = 69%; Pheterogeneity = 0.03). After removal of the

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West−Wright et al., 2009 (women) Friedenreich et al., 2009 (women) Cleveland et al., 2012 (women) Irwin et al., 2011 (women) Emaus et al., 2010 (women) Enger et al., 2004 (women) Schmidt et al., 2013 (women) Irwin et al., 2008 (women) Dal Maso et al., 2008 (women) Rohan et al., 1995 (women) Hellmann et al., 2010 (women)

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Annals of Oncology

Table 2. Relation of physical activity to total mortality and cancer mortality among breast cancer survivors, stratified by BMI, menopausal status and ER status Stratification criterion

6 6

0.70 [0.55, 0.89] 0.77 [0.64, 0.92]

52 0

0.54

3 3

0.77 [0.58, 1.04] 0.65 [0.37, 1.16]

0 65

0.53

3 3

0.67 [0.36, 1.25] 0.75 [0.54, 1.05]

33 44

0.80

4 3

1.03 [0.71, 1.48] 0.68 [0.47, 0.99]

15 0

0.10

2 2

0.72 [0.56, 0.92] 0.62 [0.20, 1.91]

0 83

0.85

1 1

0.46 [0.26, 0.80] 0.33 [0.13, 0.83]

-

-

3 3

0.64 [0.48, 0.86] 0.60 [0.39, 0.93]

27 53

0.99

2 2

0.73 [0.61, 0.87] 0.74 [0.66, 0.84]

0 0

0.85

1 1

0.84 [0.68, 1.03] 0.70 [0.62, 0.79]

-

-

2 2

0.94 [0.60, 1.49] 0.71 [0.61, 0.83]

43 0

0.18

3 3

0.46 [0.23, 0.92] 0.73 [0.59, 0.89]

89 0

0.28

1 1

0.79 [0.67, 0.93] 0.66 [0.52, 0.84]

-

9 9

0.68 [0.58, 0.81] 0.74 [0.65, 0.84]

42 0

0.57

5 5

0.74 [0.64, 0.86] 0.70 [0.57, 0.87]

0 28

0.92

4 4

0.82 [0.68, 0.98] 0.72 [0.63, 0.81]

0 6

0.21

6 5

0.96 [0.74, 1.23] 0.71 [0.62, 0.82]

25 0

0.04

5 5

0.60 [0.45, 0.81] 0.74 [0.53, 1.03]

75 39

0.42

2 2

0.64 [0.39, 1.08] 0.54 [0.29, 1.00]

70 51

0.68

-

RR, relative risk; CI, confidence interval; PA, physical activity; BMI, body mass index; ER, estrogen receptor. *The P-values for difference across strata were obtained using meta-regression comparing the model including the stratification variable as explanatory variable with the null model not including any explanatory variables.

Kuiper et al. study [26] (lowest risk estimate) from this analysis, the heterogeneity was no longer statistically significant (Pheterogeneity = 0.08). The funnel plot, Egger’s test (P = 0.48), and Begg’s test (P = 0.11) indicated no evidence for publication bias for total mortality. For the post-diagnosis physical activity and colorectal cancer mortality relation, visual inspection of the funnel plot revealed asymmetry and Egger’s and Begg’s tests were both statistically significant (Egger’s test: P = 0.001; Begg’s test: P = 0.02). Omission of one study at a time did not materially alter the results (S1 for total mortality, S2 for cancer mortality). Examining only studies that measured postdiagnosis physical activity within 1–2 years after colorectal cancer diagnosis did not appreciably alter the findings (total mortality: RR = 0.53; 95% CI = 0.42–0.67; cancer mortality: RR = 0.51; 95% CI = 0.26–1.03).

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Dose–response relation between physical activity and total mortality and cancer mortality. Each 5, 10, or 15 MET-h/week increase in pre-diagnosis physical activity was related to a 7% (95% CI = 1–13%), 14% (95% CI = 1–25%), and 20% (95% CI = 2–35%) reduction in risk of total mortality among colorectal cancer survivors, respectively (Table 3). By comparison, each 5, 10, or 15 MET-h/week increase in postdiagnosis physical activity was associated with a 15% (95% CI = 10–19%), 28% (95% CI = 20–35%), and 38% (95% CI = 28–47%) lower risk of total mortality, respectively. The dose-response analyses of pre- and post-diagnosis physical activity in relation to cancer mortality revealed results similar to those seen for total mortality, although relations of pre-diagnosis physical activity to colorectal cancer mortality were statistically non-significant (Table 3).

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Pre-diagnosis PA BMI <25 kg/m² ≥25 kg/m² Menopausal status Pre-menopausal Post-menopausal Tumor ER status ER positive ER negative Post-diagnosis PA BMI <25 kg/m² ≥25 kg/m² Menopausal status Pre-menopausal Post-menopausal Tumor ER status ER positive ER negative Pre- and post-diagnosis PA combined BMI <25 kg/m² ≥25 kg/m² Menopausal status Pre-menopausal Post-menopausal Tumor ER status ER positive ER negative

Total mortality Cancer mortality Number of RR [95% CI] I 2 (%) *P-value Number of RR [95% CI] I 2 (%) *P-value datasets included (high versus low PA) datasets included (high versus low PA)

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Annals of Oncology

Table 3. Dose–response relation of physical activity to total mortality and cancer mortality among breast and colorectal survivors for an increase of 5, 10, or 15 MET-h/week of physical activity

RR [95% CI] of total mortality

Colorectal cancer survivors Number of datasets included

RR [95% CI] of total mortality

6 6 6

0.93 [0.89, 0.98] 0.87 [0.79, 0.96] 0.81 [0.70, 0.94]

3 3 3

0.93 [0.87, 0.99] 0.86 [0.75, 0.99] 0.80 [0.65, 0.98]

4 4 4

0.87 [0.80, 0.94] 0.76 [0.64, 0.89] 0.66 [0.52, 0.84]

5 5 5

0.85 [0.81, 0.90] 0.72 [0.65, 0.80] 0.62 [0.53, 0.72]

5 5 5

0.92 [0.85, 0.99] 0.84 [0.73, 0.99] 0.78 [0.62, 0.98]

3 3 3

0.94 [0.87, 1.00] 0.87 [0.76, 1.00] 0.82 [0.66, 1.01]

4 4 4

0.94 [0.92, 0.97] 0.89 [0.85, 0.94] 0.84 [0.78, 0.91]

4 4 4

0.86 [0.81, 0.92] 0.75 [0.65, 0.85] 0.65 [0.53, 0.79]

RR, relative risk; CI, confidence interval; PA, physical activity; MET, metabolic equivalent of task.

potential modifying factors We performed subanalyses to examine whether the relations of pre- and post-diagnosis physical activity to total mortality among survivors of breast or colorectal cancers were potentially modified by the type of physical activity assessment, number of study participants, number of cases, study geographic location, and adjustments for tumor stage, cancer treatment, smoking, and adiposity. The relation of pre-diagnosis physical activity to total mortality among breast cancer survivors did not differ according to potential effect modifying variables (Table 4). The inverse association between post-diagnosis physical activity and total mortality among breast cancer survivors appeared to be slightly more pronounced in studies with interview-based (RR = 0.42; 95% CI = 0.32–0.57) than self-reported physical activity assessments (RR = 0.59; 95% CI = 0.50–0.69), although the formal test for heterogeneity was only borderline statistically significant (Pdifference = 0.05). The association between pre-diagnosis physical activity and total mortality among colorectal cancer survivors was not affected by potential effect modifying variables (Table 5). The association between post-diagnosis physical activity and total mortality among colorectal cancer survivors differed by study geographic region (Pdifference = 0.02), with summary RRs of 0.55 (95% CI = 0.50–0.69) and 0.75 (95% CI = 0.60, 0.94) for studies conducted in North America and Australia, respectively. However, that effect modification was based on only five studies from North America and one study from Australia.

 | Schmid and Leitzmann

change in physical activity from pre- to post-diagnosis We pooled the data from three studies that provided risk estimates for the relations of change in physical activity from pre-to post-diagnosis to mortality in survivors of breast cancer [11, 17] and colorectal cancer [22]. Compared with survivors of breast or colorectal cancer who did not change their physical activity level from pre- to post-diagnosis or were inactive/insufficiently active before diagnosis, those who increased their physical activity level showed a statistically significant decreased risk of total mortality (RR = 0.61; 95% CI = 0.46–0.80) and a suggestive decreased risk of cancer mortality (RR = 0.71; 95% CI = 0.45–1.12; Figure 4). In contrast, individuals who decreased their physical activity level from pre- to post-diagnosis displayed statistically non-significant increased risks of total mortality (RR = 1.72; 95% CI = 0.76–3.87) and cancer mortality (RR = 1.28; 95% CI = 0.87–1.90) when compared with those who did not change their physical activity level or were inactive/insufficiently active before diagnosis.

discussion Our meta-analysis showed that engaging in the approximate equivalent of 150 min of at least moderate physical activity per week after cancer diagnosis was associated with a 24% reduced risk of total mortality among breast cancer survivors. Among colorectal cancer survivors, a similar dose of post-diagnosis

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Total mortality Pre-diagnosis PA Increase of 5 MET-h/week Increase of 10 MET-h/week Increase of 15 MET-h/week Post-diagnosis PA Increase of 5 MET-h/week Increase of 10 MET-h/week Increase of 15 MET-h/week Cancer mortality Pre-diagnosis PA Increase of 5 MET-h/week Increase of 10 MET-h/week Increase of 15 MET-h/week Post-diagnosis PA Increase of 5 MET-h/week Increase of 10 MET-h/week Increase of 15 MET-h/week

Breast cancer survivors Number of datasets included

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Annals of Oncology

Table 4. Relation of physical activity to total mortality among survivors of breast cancer, stratified by selected characteristics Stratification criterion

RR [95% CI] (high versus low PA)

I 2 (%)

*P- value

5 6

0.78 [0.66, 0.94] 0.76 [0.63, 0.92]

40 53

0.87

7 4

0.81 [0.68, 0.95] 0.73 [0.60, 0.88]

44 42

0.44

5 6

0.81 [0.63, 1.05] 0.76 [0.67, 0.86]

61 19

0.53

4 7

0.80 [0.69, 0.92] 0.76 [0.63, 0.91]

0 57

0.76

5 6

0.77 [0.64, 0.93] 0.78 [0.65, 0.93]

46 48

0.90

7 4

0.81 [0.71, 0.93] 0.71 [0.56, 0.90]

31 53

0.32

4 7

0.75 [0.63, 0.90] 0.78 [0.66, 0.93]

0 57

0.82

4 7

0.72 [0.59, 0.88] 0.81 [0.69, 0.94]

32 43

0.39

8 3

0.74 [0.65, 0.84] 0.88 [0.67, 1.15]

27 56

0.18

2 2

0.59 [0.50, 0.69] 0.42 [0.32, 0.57]

0 0

0.05

1 3

0.33 [0.15, 0.73] 0.54 [0.44, 0.66]

– 35

0.26

2 2

0.48 [0.32, 0.72] 0.53 [0.39, 0.71]

17 65

0.70

2 2

0.48 [0.38, 0.61] 0.51 [0.30, 0.86]

0 52

0.25

3 1

0.50 [0.37, 0.67] 0.54 [0.37, 0.79]

55 –

0.80

1 3

0.60 [0.50, 0.72] 0.46 [0.37, 0.58]

– 0

0.08

RR, relative risk; CI, confidence interval; PA, physical activity *The P-values for difference across strata were obtained using meta-regression comparing the model including the stratification variable as an explanatory variable with the null model not including any explanatory variables.

physical activity was related to a 28% decreased risk of total mortality. A comparable amount of physical activity performed pre-diagnosis was related to a 13% reduced total mortality risk

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among breast cancer survivors and a 14% decreased total mortality risk among colorectal cancer survivors. In addition, we found that an increase in physical activity from pre- to post-

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Pre-diagnosis physical activity Type of physical activity assessment Self-report Interview Number of study participants <2000 study participants ≥2000 study participants Number of cases <350 cases ≥350 cases Study geographic region Europe North America Number of adjustment factors >8 adjustment factors ≤8 adjustment factors Adjustment for tumor stage Adjusted for tumor stage Not adjusted for tumor stage Adjustment for cancer treatment Adjusted for cancer treatment Not adjusted for cancer treatment Adjustment for smoking Adjusted for smoking Not adjusted for smoking Adjustment for adiposity Adjusted for adiposity Not adjusted for adiposity Post-diagnosis physical activity Type of physical activity assessment Self-report Interview Number of study participants <2000 study participants ≥2000 study participants Number of cases <350 cases ≥350 cases Number of adjustment factors >8 adjustment factors ≤8 adjustment factors Adjustment for cancer treatment Adjusted for cancer treatment Not adjusted for cancer treatment Adjustment for smoking Adjusted for smoking Not adjusted for smoking

Number of datasets included

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Table 5. Relation of physical activity to total mortality among survivors of colorectal cancer, stratified by selected characteristics Stratification criterion

*P -value

RR [95% CI] (high versus low PA)

3 1

0.73 [0.61, 0.87] 0.77 [0.58, 1.03]

0 –

0.74

3 1

0.76 [0.61, 0.94] 0.72 [0.58, 0.89]

0 –

0.74

3 1

0.76 [0.61, 0.94] 0.72 [0.58, 0.89]

0 –

0.74

2 2

0.75 [0.50, 1.12] 0.74 [0.62, 0.87]

32 0

0.97

1 3

0.95 [0.57, 1.59] 0.72 [0.61, 0.84]

– 0

0.32

3 1

0.73 [0.61, 0.87] 0.77 [0.58, 1.03]

0 –

0.74

5 1

0.55 [0.41, 0.74] 0.58 [0.47, 0.71]

49 –

0.87

4 2

0.49 [0.38, 0.64] 0.66 [0.51, 0.84]

0 64

0.11

5 1

0.55 [0.46, 0.64] 0.75 [0.60, 0.94]

0 –

0.02

5 1

0.55 [0.41, 0.74] 0.58 [0.47, 0.71]

49 –

0.87

4 2

0.58 [0.43, 0.78] 0.56 [0.46, 0.68]

51 0

0.71

4 2

0.62 [0.52, 0.75] 0.41 [0.26, 0.64]

34 0

0.10

RR, relative risk; CI, confidence interval; PA, physical activity. *The P-values for difference across strata were obtained using meta-regression comparing the model including the stratification variable as an explanatory variable with the null model not including any explanatory variables.

diagnosis was associated with reduced risk of total mortality. The apparent protection from total mortality afforded by physical activity was observed in analyses with and without adjustments for tumor stage, cancer treatment, smoking, and adiposity, and it was evident in both large and small studies, in studies using self-reported and interview-based physical activity assessments, and in studies from different countries. Among breast cancer survivors, the benefit of physical activity was evident for both lean and overweight women, for pre- and postmenopausal women, and for ER positive and negative tumors. These findings strongly support current physical activity

 | Schmid and Leitzmann

guidelines for cancer survivors, which endorse 150 min of moderate activity per week [36]. Numerous biologic mechanisms potentially explain the observed apparent protective effect of physical activity on total and cancer mortality among cancer survivors. For example, intervention studies in breast cancer survivors show that exercise lowers C-reactive protein and blood pressure [37], facilitates weight loss [38], decreases insulin and insulin-like growth factors [39], and improves immune function [40], physiologic processes that plausibly mediate the inverse physical activity and mortality relation in cancer survivors. In addition, physical activity lowers

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Pre-diagnosis physical activity Type of physical activity assessment Self-report Interview Number of study participants <2000 study participants ≥2000 study participants Number of cases <350 cases ≥350 cases Number of adjustment factors >8 adjustment factors ≤8 adjustment factors Adjustment for cancer treatment Adjusted for cancer treatment Not adjusted for cancer treatment Adjustment for smoking Adjusted for smoking Not adjusted for smoking Post-diagnosis physical activity Number of study participants <2000 study participants ≥2000 study participants Number of cases <350 cases ≥350 cases Study geographic region North America Australia Number of adjustment factors >8 of adjustment factors ≤8 of adjustment factors Adjustment for cancer treatment Adjusted for cancer treatment Not adjusted for cancer treatment Adjustment for smoking Adjusted for smoking Not adjusted for smoking

I 2 (%)

Number of datasets included

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Annals of Oncology

Authors, year (Gender)

Relative risk [95% CI]

Increase in PA from pre− to post−diagnosis (total mortality) Meyerhardt et al., 2006 (women)

0.51 [0.30, 0.85]

Irwin et al., 2008 (women)

0.55 [0.22, 1.38]

Irwin et al., 2011 (women)

0.67 [0.46, 0.96]

Random effects model

0.61 [0.46, 0.80]

Irwin et al., 2011 (women)

1.06 [0.73, 1.54]

Meyerhardt et al., 2006 (women)

1.23 [0.79, 1.91]

Irwin et al., 2008 (women)

3.95 [ 1.45, 6.17]

Random effects model

1.72 [0.76, 3.87]

Increase in PA from pre− to post−diagnosis (cancer mortality) Meyerhardt et al., 2006 (women)

0.48 [0.24, 0.97]

Irwin et al., 2008 (women)

0.82 [0.29, 2.34]

Irwin et al., 2011 (women)

0.91 [0.51, 1.64]

Random effects model

0.71 [0.45, 1.12]

Decrease in PA from pre− to post−diagnosis (cancer mortality) Irwin et al., 2011 (women)

1.06 [0.59, 1.88]

Meyerhardt et al., 2006 (women)

1.32 [0.74, 2.34]

Irwin et al., 2008 (women)

3.69 [0.88, 15.92]

Random effects model

1.28 [0.87, 1.90]

0.25

0.50

1.00

2.00

4.00

Relative risk (log scale) Figure 4. Forest plot of the relations of change in physical activity (PA) from pre- to post-diagnosis to total mortality and cancer mortality.

endogenous estrogen levels among healthy postmenopausal women [41] and an etiologic pathway involving decreased levels of endogenous estrogens among physically active women may also be operative after breast cancer diagnosis. This may partly explain the pronounced inverse relations of physical activity to breast cancer mortality in post-menopausal women seen in our meta-analysis. Our findings showed that physical activity performed before cancer diagnosis was related to reduced risks of both total and cancer mortality. One possible explanation for the reduced risk

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of mortality observed for pre-diagnosis physical activity is that individuals who are physically active before being diagnosed with cancer are predisposed to biologically less aggressive tumors [22]. Moreover, pre-diagnosis physical activity may beneficially affect the treatment process because it leads to improved functional capacity to tolerate and complete surgery and adjuvant treatment [27]. Individuals who are physically active before diagnosis remain physically active during the post-diagnosis period [42] as shown by positive correlations between pre-diagnosis physical activity

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Decrease in PA from pre− to post−diagnosis (total mortality)

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 | Schmid and Leitzmann

association between post-diagnosis physical activity and colorectal cancer mortality should be interpreted with caution because we found evidence for publication bias regarding that relation. The primary strength of our meta-analysis is its comprehensiveness which included three issues not dealt with in previous meta-analyses [28, 29]: (1) quantification of the amount of physical activity needed for protection against mortality among cancer survivors; (2) examination of change in physical activity from pre- to post-diagnosis in relation to mortality among cancer survivors; (3) performance of meta-regression to evaluate potential sources of heterogeneity among studies. Further strengths of our meta-analysis are that it focused on welldesigned prospective studies and that it was characterized by a large sample size, yielding valid and precise summary RRs for physical activity. One potential limitation of our meta-analysis is that the associations reported in individual studies may have been hampered by reverse causality which could have occurred if cancer patients had been less physically active due to symptoms of the disease at the time of physical activity assessment. However, studies that excluded cancer patients shortly before or after cancer diagnosis in sensitivity analyses reported that results were not materially altered by that procedure [11, 22, 24]. In addition, we performed separate meta-analyses that were restricted to studies with postdiagnosis physical activity measured within 1–2 years of breast or colorectal cancer diagnosis. We observed no change in the results, indicating that our findings are not likely due to the effects of reverse causation. An additional shortcoming of our study is variability in the range of physical activity levels reported in the individual studies. We found no meaningful heterogeneity among studies regarding the associations between pre- and post-diagnosis physical activity and total mortality among breast and colorectal cancer survivors. Although the studies included in our meta-analysis adjusted for numerous confounding variables, we cannot rule out potential residual confounding or confounding by unmeasured factors, such as adherence to therapy. However, because the summary risk estimates for physical activity in our meta-analysis did not appreciably differ among studies that adjusted for cancer therapy, tumor stage, and adiposity, and those that did not, we assume that such confounding would not be substantial. An additional potential limitation of our study is measurement error associated with self-reported or interview-based physical activity assessments. However, because the physical activity data were gathered before the occurrence of death, any random measurement error in physical activity assessment would tend to underestimate the association between physical activity and mortality. In summary, we found that engaging in physical activity before or after cancer diagnosis was associated with statistically significant decreased risks of total and cancer mortality among breast and colorectal cancer survivors. We also observed that an increase in physical activity from pre- to post-diagnosis was associated with reduced risk of cancer mortality. Future studies should examine how physical activity participation could best be incorporated into daily routines after cancer treatment. In the meantime, physicians should consider counseling cancer survivors to adopt a physically active lifestyle, taking into account the medical and physical condition of their cancer patients.

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and post-diagnosis physical activity among colorectal cancer survivors (correlation coefficient: 0.4) [24] and breast cancer survivors (correlation coefficient: 0.5) [20]. One study of breast cancer survivors [43] that was not included in the current metaanalysis because the study population overlapped with that from a more recent study [19] reported that adjustment for prediagnosis physical activity did not change the association between post-diagnosis physical activity and breast cancer mortality. Likewise, two studies among colorectal cancer survivors [22, 24] adjusted for pre-diagnosis physical activity, which did not affect the relation of post-diagnosis physical activity to colorectal cancer mortality. One of those studies [22] also reported that adjustment for pre-diagnosis physical activity did not alter the association between post-diagnosis physical activity and total mortality [22]. This suggests that the decreased risk of mortality seen with post-diagnosis physical activity among breast and colorectal cancer survivors is independent of prediagnosis physical activity levels. However, none of the other studies included in the meta-analysis herein mutually adjusted for pre- and post-diagnosis physical activity. Thus, the inverse relation of post-diagnosis physical activity to mortality we observed among cancer survivors could also partly reflect the influence of increased pre-diagnosis physical activity. For some cancers, predominantly those with high survival rates, the leading causes of death are often distinct from those related to the primary cancer because with advancing age, the risk for comorbidities increases [2, 44, 45]. Thus, enhanced engagement in physical activity after diagnosis among cancer survivors may exert a beneficial effect on biologic pathways involved in the development of comorbidities, even though such conditions may not strongly affect cancer recurrence and cancer mortality [22]. Although individuals reduce their exercise participation during cancer therapy [23, 42], patients report that their physical function and quality of life are almost identical to the general population 1 year after surgery [46]. After treatment, cancer patients may be more motivated to change their behavior and to adopt a healthy lifestyle. We found that increasing physical activity engagement from pre- to post-diagnosis was associated with reduced mortality risk among cancer survivors, which emphasizes the importance of physical activity participation after cancer treatment. We are aware of two previous meta-analyses of the associations between physical activity and mortality among survivors of breast cancer [28] and colorectal cancer [29]. The previous meta-analysis of physical activity and breast cancer survival [28] was based on six studies and did not find a statistically significant relationship between pre-diagnosis physical activity and breast cancer mortality but was able to report reduced risks of total and breast cancer mortality for post-diagnosis physical activity. Our meta-analysis included 12 additional studies [5, 6, 9, 12–20] on physical activity and breast cancer survival with 33 684 additional breast cancer cases. Moreover, we included one article [19] that provided the most updated data from the Nurses’ Health Study (NHS) and the Life After Cancer Epidemiological (LACE) Study. The previous meta-analysis of physical activity and colorectal cancer survival reported inverse relations of both pre- and post-diagnosis physical activity to total and colorectal cancer mortality [29]. Our finding of an inverse

Annals of Oncology

Annals of Oncology

disclosure The authors have declared no conflicts of interest.

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